Endocrine Abstracts (2004) 7 OC1

Allopregnanolone is involved in reduced HPA axis responses to immune challenge in late pregnancy

PJ Brunton, CEL Harrison & JA Russell


School of Biomedical & Clinical Laboratory Sciences, University of Edinburgh, Edinburgh, UK.


In late pregnancy, the hypothalamo-pituitary-adrenal (HPA) axis is less responsive to immune challenge(1). Circulating and brain levels of allopregnanolone (AP), a neuroactive steroid and allosteric enhancer at inhibitory GABAA receptors, increase during pregnancy(2) and AP treatment attenuates stress-induced HPA activity in male rats(3). Here we sought a role for AP in attenuated HPA axis responses to interleukin-1-beta (IL-1B) in pregnant rats. Conscious pregnant (day 21) and virgin Sprague-Dawley rats were blood-sampled via a jugular vein cannula (implanted -5 days, under halothane) for ACTH and corticosterone RIA before and after IL-1B (500ng/kg i.v., all rats). Experiment 1: To block AP production, rats were pretreated with finasteride (a 5-alpha reductase inhibitor; 25mg/kg s.c.) or vehicle (20% ethanol in sesame oil, s.c.), 20h and 2h before IL-1B. Experiment 2: Virgin rats were treated 20h and 2h before IL-1B with AP (3mg/kg and 1mg/kg, respectively s.c.) or vehicle; while pregnant rats were also treated with finasteride (as before) and AP (as before) or vehicle. Rats were killed 4h after IL-1B and brains removed for CRH mRNA in situ hybridisation. IL-1B significantly increased ACTH and corticosterone secretion, and CRH mRNA expression in the paraventricular nucleus in virgin controls, but these HPA responses were attenuated in the pregnant controls (ACTH: 3.3-fold, p<0.001, vs 1.3-fold, n.s.). Finasteride treatment did not affect HPA responses to IL-1B in virgin rats, however reinstated ACTH (2.2-fold increase, p<0.05), corticosterone and CRH neurone responses in the pregnant rats. Allopregnanolone treatment reduced ACTH (by 44%) and corticosterone responses in virgin rats and reversed the effects of finasteride in pregnant rats. The data strongly support a role for AP in restraining HPA activity after immune challenge in pregnancy. [(1)Brunton PJ et al, Stress 2002, 5: 52; (2)Concas A et al, Eur J Pharmacol 1999, 375: 225-35; (3)Patchev VK et al, Neuropsychopharm (1996), 15:533-540] [Support:BBSRC].

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